This program will continue to develop practical, flexible strategies for the enantioselective synthesis of six to nine membered ring ethers and apply the new strategies to the total synthesis of structurally novel and biologically important natural products. During the course of this investigation, new synthetic technologies will be explored for the asymmetric construction of cyclic ethers and carbocycles based on establishing acyclic stereochemical arrays followed by ring closure. During the next grant period the total synthesis of brevetoxin A will be completed. The synthesis of sorangicin A, brevenal, hemibrevetoxin B, sclerophytin A, brianthein A, and verillin will also be pursued. Important analogs of these natural products will also be prepared. A novel 3- component assembly of 1, 1'-disubstituted ether linkages, a new asymmetric acetate aldol, and an anti-glycolate aldol will be further developed and exploited. The dianioic Claisen rearrangement will be further developed for construction of quaternary stereogenic centers and applied to brianthein A and verillin. The total synthesis of brevetoxin A, sorangicin A, brevenal sclerophytin A, brianthein A and verillin will be carried out. New enantioselective methods for the synthesis of cyclic ethers and carbocycles will be investigated.